BACKGROUND : Previous work indicates that mutant-allele tumor heterogeneity (MATH), estrogen receptor alpha (ERα) expression, and human papillomavirus (HPV) status provide prognostic utility in head and neck squamous cell carcinoma (HNSCC). We sought to assess whether the combination of these three objective biomarkers could provide better prognostication for patients who receive chemoradiotherapy (CRT).

METHODS : 156 patients (75 oral cavity, 44 oropharyngeal and 37 laryngeal squamous cell carcinoma cancer patients) who received CRT as primary therapy or adjuvant to surgery were identified from The Cancer Genome Atlas (TCGA). MATH values were calculated from TCGA whole exome sequencing data, HPV status was determined by mapping RNA-seq reads, and ERα expression was determined from ESR1 mRNA expression data. Relationships among clinical characteristics were assessed by Fisher exact tests. Relationships of clinical characteristics and MATH, ERα and HPV to overall survival were evaluated with Cox proportional hazard analysis.

RESULTS : The combination of poor-prognosis values for all 3 biomarkers (high MATH, low ERα and HPV-negative status) has a predicted hazard ratio of 28.2 (95% CI: 5.4-148, p = 0.0001) versus the combination of their good-prognosis values (low MATH, high ERα and HPV-positive status). Addition of N classification to the combination of these three biomarkers added further prognostic value.

CONCLUSIONS : A combination of these three biomarkers, readily determined on pretreatment biopsy specimens, can stratify patients into prognostic groups. Their application potentially offers numerous opportunities to optimize treatment or explore de-intensification strategies in the clinical trial setting.